Elucidation of Pathways Driving Asthma Pathogenesis: Development of a Systems-Level Analytic Strategy

Abstract

Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1–6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.

Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways

“…Heterogeneity in asthma is well described and there are multiple proposed asthma phenotypes based on age, the presence of concurrent allergies, elevation in serum IgE, the cellularity of BAL fluid (eosinophil- or neutrophil-enriched), response to corticosteroid therapy, and obesity [29, 30]. Our study examines two distinct groups of asthmatic subjects: those with relatively mild airflow obstruction who were well controlled on either ICS therapy or with no CS therapy at all, and those with more severe airflow obstruction and a need for OCS therapy.…”

The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage

“…It is recognized that between birth and weaning, multiple innate and adaptive immune mechanisms that are central to inflammatory pathways triggered by infectious and atopic stimuli are transiting at highly variable rates from the functionally attenuated fetal-like state toward adult-equivalent levels of immune competence (reviewed by Walker et al 26 ). Of particular relevance to this discussion are observations linking sluggish postnatal maturation kinetics with increased susceptibility to subsequent development of atopic and/or asthma-related phenotypes.…”

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re‐occurrence of foetal type 2 signalling? The MeDALL hypothesis

“…IL‐4 production at 3 months is associated with IgE levels at 5 years . Birth cohort studies are relevant for the investigation of the environmental and lifestyle determinants of asthma and IgE‐associated diseases as well as the absence of such diseases (Fig. ).…”